Abstract [en]

Background: The two-gene expression ratio HOXB13:IL17BR, originally from a microarray analysis, has been shown to be indicative of clinical outcome in the setting of adjuvant tamoxifen monotherapy of breast cancer, with a high ratio associated with decreased disease-free survival. Analysis of a cohort of breast cancer patients randomized to 2 or 5 years of adjuvant tamoxifen therapy showed that the two-gene ratio and expression of the HOXB13 gene alone were predictive of the benefit of prolonged tamoxifen treatment. Patients with tumors expressing HOXB13 at high levels were unresponsive to prolonged adjuvant treatment, suggesting that this gene is involved in tamoxifen resistance. It is suggested that a high two-gene ratio may indicate impaired ER signaling, which is known to predict resistance to tamoxifen. To our knowledge, there are no studies investigating the HOXB13 protein levels in breast cancer.

Methods: We have analyzed the protein expression of HOXB13 with immunohistochemistry in tumor samples from 912 postmenopausal node negative breast cancer patients randomized to 2 years of tamoxifen or no endocrine treatment. After 2 years, recurrence-free patients were randomized to 3 more years of tamoxifen, or no further therapy. This selection enabled us to investigate the treatment predictive value of HOXB13.

Results: Data on HOXB13 protein expression were obtained from 866 patients (see table). Tamoxifen treated patients with estrogen receptor (ER) positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (hazard ratio (HR) 0.37, 95% CI 0.23-0.60, p=0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the distant recurrence-free survival compared to the untreated patients (HR=0.83, 95% CI 0.45-1.54, p=0.55). The interaction between HOXB13 expression and benefit from tamoxifen was statistically significant (p=0.046). HOXB13 did not have any prognostic value among systemically untreated patients.